Poly(vinyl alcohol) (PVA) is known to form excellent biocompatible hydrogels. Currently available methods of making poly(vinyl alcohol) (PVA)-based materials have focused on hydrogels prepared using freeze-thawing techniques (see Ku, D. N. Poly(vinyl alcohol) hydrogel. U.S. Pat. No. 6,231,605; Ku, D. N.; Braddon, L. G.; Wootton, D. M. Poly(vinyl alcohol) cryogel. U.S. Pat. No. 5,981,826; and Inoue, T. Gelled vinyl alcohol polymers and articles therefrom. U.S. Pat. No. 3,875,302).
The scientific literature also has focused largely on the properties of freeze-thawed PVA hydrogels (see Hassan, C. M., Peppas, N. A. Advances in Polymer Science 2000, 153, 37-65). Other studies have investigated PVA hydrogels prepared using mixed solvents (see Hong, P.-D., Chou, C.-M., Chuang, W.-T. Journal of Applied Polymer Science 2001, 79, 1113-1120; Bodugoz-Senturk, H., Choi, J., Oral, E.; Kung, J. H., Macias, C. E., Braithwaite, G., Muratoglu, O. K. Biomaterials 2008, 29, (2), 141-149; US Publication Nos. US 2004-0092653; US 2004-0171740; US 2006-020781; US 2007-0054990; US 2007-016754; US 2008-0274161; and US 2008-0208347). Both freeze-thawed and mixed solvent hydrogels contain only physical crosslinks comprised of PVA crystallites. No chemical crosslinkers are used.
Chemically crosslinked PVA hydrogels have been reported. PVA beads crosslinked with aldehydes for use as a water-loss agent in oil drilling fluids have been developed (Michaels, A. S. Method of Preparing Crosslinked Poly(vinyl alcohol). U.S. Pat. No. 4,385,155). PVA beads crosslinked with cyclic crosslinking agents for use in gel chromatography also have been developed (Murayama, N., Sakagami, T. Crosslinked Polyvinyl Alcohol Gel. U.S. Pat. No. 4,314,032).
Some approaches combined chemical and physical crosslinking. In the work of Williams et al., a solution of PVA in a mixture of DMSO and water is freeze-thawed, subsequently gamma-irradiated, and then the surface is crosslinked with boric acid (Williams, P. F., Ngo, C., DeMaria, C. Wear Resistant Hydrogel For Bearing Application. 7282165, 2007). Another approach is described in Muratoglu et al., U.S. Pat. No. 7,235,592). Recently, Muratoglu et al. have published WO 2008/131251.
PVA and copolymers of PVA are known (see for example Cauich-Rodriguez et al. J Appl Polym Sci 82 (14) 3578-3590; Horkay macromolecules 1993 (26) 3375); and chemically crosslinked PVA hydrogels are also known (Bourke S L, Al-Khalili M, Briggs T, Michniak B B, Kohn J, Poole-Warren L A. A Photo-Crosslinked Poly(vinyl Alcohol) Hydrogel Growth Factor Release Vehicle for Wound Healing Applications. AAPS PharmSci. 2003; 5 (4)). There has been much discussion of PVA based hydrogels (Hassan Advances in Polymer Science 2000) and their blends and IPNs resulting from these materials.
Attachment of an active molecule to a hydrogel is known (See B. Ratner et al. “Biomaterials Science (Second Edition)” (2004)). A mono-functional PEG molecule can be coupled on one end to a therapeutic. For example, a mono-functional PEG molecule can be coupled on one end of a protein or an amino acid conjugate, while the other end contains an acrylate group. This molecule could act both as the mono-functional PEG component and a sustained drug release agent.
Crosslinkers
Various crosslinkers have been disclosed in the literature for crosslinking polymers, e.g. novel thiol PEG crosslinkers (Vanderhooft biomacromolecules 2007 8(9) 2883) as well as EGDMA crosslinkers used with VAc, acrylic acid and methacrylic acid (Ranjha Pakistan Journal of Pharmaceutical Sciences 1999 12(1) 33-41). Hydrogels also have been formed by partially hydrolyzed PVAc where the crosslinking occurred between the hydroxyl groups and hydrolysis level controlled the adhesion to tissue (Guo biomacromolecules 2008 9(6) 1637). PVA has been shown to crosslink using glutaraldehyde (Horkay macromolecules 1994 27 1795), acrylamide groups (Martens Chemistry of Matter 2007 19(10) 2641. In the patent literature PVA has been crosslinked using polyoxirane (U.S. Pat. No. 4,598,122, Polyoxirane crosslinked polyvinyl alcohol hydrogel contact lens).
Surface Friction
A number of authors have discussed surface friction of hydrogels, and the weaknesses of existing materials relative to cartilage (R. J. Covert, R. D. Ott, D. N. Ku, Friction characteristics of a potential articular cartilage biomaterial. Wear 255 (2003) and A. G. McNickle, M. T. Provencher, B. J. Cole, Overview of Existing Cartilage Repair Technology. Sports Med Arthrosc Rev 16(4), 196-201(2008)).
Hydrolysis of PVAc to PVA Hydrogels
PVA microspheres can be manufactured by crosslinking VAc in emulsion polymerization, and then hydrolyzing the subsequent PVAc-base “organogel”. See for example, Ryoichi Murakami, Hiroshi Hachisako, Kimiho Yamada and Yoshiaki Motozato, Polym. J., 25, 205 (1993), which describes the preparation of PVA microspheres by creating PVAc microspheres then hydrolyzing using methanol in an aqueous solution of sodium sulfate. Another method for making particles describes a crosslinked polyvinyl alcohol gel obtained by copolymerizing vinyl acetate and a crosslinking agent and hydrolyzing the product (Murayama and Sakagami, U.S. Pat. No. 4,314,032, Crosslinked polyvinyl alcohol gel). However, this is not the only way to make PVA microspheres, as David Lee Wise (2000) “Handbook of pharmaceutical controlled release technology” points out. In addition, the idea of using VAc and then hydrolyzing has been disclosed as part of a copolymer (Xiao, Carbohydrate polymers 64(1) 37-40 and Velazco-Diaz, Industrial Engineering and Chemical Research 2005 44(18) 7092-7097, Ranjha, Pakistan Journal of Pharmaceutical Sciences 1999 12(1) 33-41). Baird et al. (U.S. Pat. No. 4,224,262 Crosslinked copolymer of an olefin and vinyl alcohol) described a crosslinked hydrogel formed by using a copolymer of an olefin and vinyl ester and crosslinking using irradiation with subsequent hydrolysis.
Hydrogels having physical crosslinks (thetagels) prepared without chemical crosslinkers, irradiation and thermal cycling are disclosed in U.S. Pat. Nos. 7,619,009 and 7,485,670.
Pendant Chains
Pendant chains with specific functionality have been discussed in the context of allowing crosslinking (Martens Chemistry of Matter 2007 19(10) 2641) and (U.S. Pat. No. 5,210,111-Crosslinked hydrogels derived from hydrophilic polymer backbones) which discusses generating a PVA backbone and pendant side-groups, although points out the complexity of the chemistry involved. This PVA backbone could be formed in to a hydrogel using conventional PVA crosslinkers, such as glutaraldehyde as described above. The target application for this patent is contact lenses. Pendant side groups have been known to be used to modify surface friction in hydrogels, see for example Ohsedo, et al. “Surface Friction of Hydrogels with Well-Defined Polyelectrolyte Brushes” Langmuir 2004 20(16), 6549-6555.
General Hydrogel Implantables
The idea of a multi-functionality hydrogel that is composed of alcohol groups amongst others, and is implantable, has been disclosed, for example, Thomas U.S. application Ser. No. 11/969,591, CHEMICAL COMPOSITION OF HYDROGELS FOR USE AS ARTICULATING SURFACES). U.S. application Ser. No. 11/833,549, Multi-polymer Hydrogels, discusses generating IPN structures for implantation. In addition, degradable hydrogels have been shown to form from PVA chains with polymerizable pendant groups. (U.S. Pat. No. 6,710,126 Degradeable poly(vinyl alcohol) Hydrogels).